5-HT2A agonists for use in treatment of depression

Abstract

The present invention relates to agonists of the 5-HT2A serotonin receptors and their medical uses. In one aspect the invention relates to 5-HT2A agonists of formula (I). In second aspect, the invention relates to selective 5-HT2A agonists of formula (II). In another aspect, the invention relates to mixed 5-HT2A/5-HT2C agonists of formula (III). In yet another aspect, the invention relates to 5-HT2A agonists for use in the treatment of a depressive disorder, more particular a 5-HT2A agonist for the use in the treatment of treatment-resistant depression.

The invention claimed is: 
     
       1. A method of treating major depressive disorder (MDD) (also known as clinical depression, unipolar depression), melancholia, psychotic depression, antenatal depression, postnatal depression, bipolar disorder, bipolar type I disorder, bipolar type II disorder, cyclothymic disorder, dysthymic disorder or seasonal affective disorder, treatment-resistant depression disorder (TRD), severe treatment-resistant depression disorder, Alzheimer's disease, Parkinson's disease, autism, general anxiety, existential anxiety, end of life anxiety, terminal cancer related end of life anxiety, epilepsy, sleep-wake disorders, neurocognitive disorders, obsessive compulsive disorder (OCD), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), stress, acute stress disorder, Horton's headache, chronic cluster headache, migraine, general local inflammation, muscle inflammation, joint inflammation, pulmonary inflammation, asthma, arthritis, smoking cessation, alcohol cessation, cocaine cessation, heroin cessation, opioid cessation, methamphetamine cessation, general addiction therapy, eating disorders such as compulsive eating disorders, anorexia nervosa, bulimia nervosa, binge eating disorder, Pica, Rumination disorder, avoidant/restrictive food intake disorder, night eating syndrome, other specified feeding or eating disorder (OSFED), body dysmorphic disorder, purging disorder, pain, chronic pain disorders, sleep wake disorders or physical rehabilitation comprising:
 administering an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof; 
 wherein formula (I) has the structure, 
 
       
         
           
           
               
               
           
         
       
       wherein: 
       * denotes the (R) or (5) stereoisomer or any mixture thereof; 
       X is selected from the group consisting of F, Cl, Br, I, CN, S—(C 1 -C 5  alkyl), S—(C 1 -C 5  fluoroalkyl), S—(C 2 -C 5  alkenyl), S—(C 2 -C 5  fluoroalkenyl), S—(C 2 -C 5  alkynyl), S—(C 2 -C 5  fluoroalkynyl), C 1 -C 5  alkyl, C 1 -C 5  fluoroalkyl, C 2 -C 5  alkenyl, C 2 -C 5  fluoroalkenyl, C 2 -C 5  alkynyl, and C 2 -C 5  fluoroalkynyl; 
       Y 1  and Y 2  are independently selected from the group consisting of H, O, S, C 1 -C 3  alkyl, C 1 -C 3  fluoroalkyl, and halogen; 
       R 1  is not present when Y 1  is H, C 1 -C 3  alkyl, C 1 -C 3  fluoroalkyl, or halogen; 
       R 2  is not present when Y 2  is H, C 1 -C 3  alkyl, C 1 -C 3  fluoroalkyl, or halogen; 
       when present, R 1  and R 2  are independently selected from the group consisting of C 1 -C 5  alkyl, C 1 -C 5  fluoroalkyl, C 2 -C 5  alkenyl, C 2 -C 5  fluoroalkenyl, C 2 -C 5  alkynyl, C 2 -C 5  fluoroalkynyl, C 3 -C 5  cycloalkyl, and C 3 -C 5  fluorocycloalkyl; 
       z denotes the number of R 3  groups and is an integer with a value of 0, 1, 2, or 3; 
       each R 3  is independently selected from the group consisting of F, C 1 -C 3  alkyl, C 1 -C 3  fluoroalkyl, C 2 -C 3  alkenyl, and C 1 -C 3  alkynyl; and 
       R 4  is H or CH 3 ; 
       with the proviso that at least one of Y 1  or Y 2  is selected as O or S. 
     
     
       2. The method of  claim 1 , wherein X is selected from the group consisting of F, Cl, Br, I, CN, S—(C 1 -C 3  alkyl), S—(C 1 -C 3  fluoroalkyl), C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, ethynyl, fluoroethynyl, and cyclopropyl. 
     
     
       3. The method of  claim 1 , wherein X is selected from the group consisting of F, Cl, Br, I, CN, S—(C 1 -C 3  alkyl), S—(C 1 -C 3  fluoroalkyl), C 1 -C 4  alkyl, and C 1 -C 4  fluoroalkyl, preferably CF 3 . 
     
     
       4. The method of  claim 1 , wherein Y 1  and Y 2  are independently selected from the group consisting of H, O, S, halogen, and CH 3 . 
     
     
       5. The method of  claim 1 , wherein Y 1  and Y 2  are independently selected from the group consisting of O, S, and H. 
     
     
       6. The method of  claim 1 , wherein Y 1  and Y 2  are independently selected from O or S. 
     
     
       7. The method of  claim 1 , wherein R 1  and R 2  are independently not present or are independently selected from the group consisting of C 1 -C 3  alkyl, C 1 -C 3  fluoroalkyl, and C 3 -C 5  cycloalkyl. 
     
     
       8. The method of  claim 1 , wherein R 1  and R 2  are selected from the group consisting of C 1 -C 2  alkyl, C 1 -C 2  fluoroalkyl and cyclopropyl. 
     
     
       9. The method of  claim 1 , wherein z is 0 or 1, and R 3  is selected from the group consisting of F, C 1 -C 2  alkyl, and C 1 -C 2  fluoroalkyl. 
     
     
       10. The method of  claim 1 , wherein z is 0 or 1, and R 3  is independently selected from the group consisting of F, CH 3 , and CF 3 . 
     
     
       11. The method of  claim 1 , wherein * denotes (S) and R 4  is H. 
     
     
       12. The method of  claim 1 , wherein the one or more R 3  groups are present at position 2, 3 or 6 in the piperidine. 
     
     
       13. The method of  claim 1 , wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in order to treat a depressive disorder selected from a list consisting of major depressive disorder (MDD) (also known as clinical depression, unipolar depression), melancholia, psychotic depression, antenatal depression, postnatal depression, bipolar disorder, bipolar type I disorder, bipolar type II disorder, cyclothymic disorder, dysthymic disorder or seasonal affective disorder, treatment-resistant depression disorder (TRD) and severe treatment-resistant depression disorder. 
     
     
       14. The method of  claim 13 , wherein the depressive disorder is major depressive disorder (also known as clinical depression, unipolar depression). 
     
     
       15. The method of  claim 13 , wherein the depressive disorder is treatment-resistant depression disorder (TRD).